Abstract Our laboratory focuses on lipoprotein lipase (LPL)?mediated processing of triglyceride-rich lipoproteins (TRLs) in capillaries. This process, intravascular lipolysis, is essential for delivering lipid nutrients to vital tissues (e.g., the heart) and is highly relevant to plasma lipid levels and coronary artery disease risk. We discovered a protein expressed exclusively in capillary endothelial cells, GPIHBP1, that is required for intravascular lipolysis. GPIHBP1 binds LPL within the interstitial spaces and shuttles it across endothelial cells to its site of action in the capillary lumen. GPIHBP1 is also required for the margination of TRLs in capillaries and for preserving the catalytic activity of LPL. These discoveries have already transformed textbook descriptions of lipolysis, but many challenges remain. One is to define the cellular and molecular mechanisms by which the fatty acid (FA) products of TRL processing traverse endothelial cells and move into parenchymal cells. No one understands this process, in part because there were no methods for visualizing FA movement into and across capillary endothelial cells. To formulate hypotheses about the mechanisms for FA movement within tissues and to test the roles of specific genes and metabolites in this process, we are now imaging tissues with NanoSIMS. NanoSIMS uses a Cs+ beam to bombard a tissue section, releasing secondary ions that can be collected, quantified, and used to create high-resolution images of cells and tissues based solely on their isotopic content. We routinely prepare fresh TRLs enriched in 13C- or 2H-labeled triglycerides, inject them intravenously into mice, and then use NanoSIMS to create high-resolution images of 13C- and 2H-FAs as they move into and across capillary endothelial cells. We obtain backscattered electron (BSE) images on the same section. Our correlative imaging approach, which is unique in the fields of lipid metabolism and vascular biology, allows us to match the chemical information from NanoSIMS to the ultrastructural morphology provided by the BSE images. We are now positioned to identify the cellular and molecular mechanisms for the movement of lipids to vital tissues. A second challenge has been to identify additional proteins in capillary endothelial cells that are relevant to lipid metabolism; a related issue is to determine if active TRL processing alters gene expression in capillary endothelial cells. Fortunately, our GPIHBP1-specific monoclonal antibodies have made it possible to purify capillary endothelial cells from complex mixtures of cells, facilitating analyses of gene expression in capillary endothelial cells. A third challenge?and one that is particularly relevant to clinical medicine?is to explore the importance of GPIHBP1 and capillary endothelial cells to human hypertriglyceridemia. We discovered autoantibodies against GPIHBP1 in the plasma of multiple patients with hypertriglyceridemia; these autoantibodies cause disease by blocking the binding of LPL to GPIHBP1. The GPIHBP1 autoantibodies now need characterization, and the frequency of this new autoimmune/metabolic disease syndrome needs to be defined. With our reagents and assays, we are uniquely positioned to address these issues.